The development and spread of bacterial antibiotic resistance has emerged as a major public health concern. Pathogenic microbes, once easily controlled by antimicrobial drugs, now frequently fail to respond to most antibiotics, and a large effort is currently directed toward the discovery or design of novel antimicrobials. However, it is almost certainly the case that for every novel antibiotic, the microbial community already harbors at least a partial solution to the task of resistance. This proposal, in contrast to more conventional searches for novel antibiotics, seeks to identify novel antimicrobials that exhibit both high antimicrobial activity and reduced resistibility. We argue that delaying the onset of resistance should be viewed as a primary design criterion in the development of novel antimicrobials, and we propose a simple, flexible and rapid strategy for the development of multicomponent antimicrobial therapies that will meet that criterion. Employing the bacteriocins, a class of highly toxic, naturally occurring antimicrobials, as our model system, this proposal describes a generalizable three-step method to generate, screen, and isolate novel engineered bacteriocin-like molecules. Specifically, we 1) design and synthesize a library containing up to 1013 variants of colicin E3; 2) use high-throughput screening to scrutinize up to 107 variants simultaneously in order to isolate specific sequences that display antimicrobial activity; 3) assemble combinations of active variants that can be simultaneously administered against the target pathogenic strain, resulting in a delay of the onset of resistance. This approach, with its emphasis on the creation and isolation of large families of active bacteriocin compounds, represents both a powerful and a practical method for demonstrating the extent to which the co-administration of multiple related bacteriocins delays the appearance and increases the cost of resistance.